Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India.
Hum Reprod. 2012 Apr;27(4):1005-15. doi: 10.1093/humrep/der477. Epub 2012 Feb 7.
The progesterone-regulated glycoprotein glycodelin-A (GdA), secreted by the decidualized endometrium at high concentrations in primates, inhibits the maternal immune response against fetal antigens and thereby contributes to the tolerance of the semi-allogenic fetus during a normal pregnancy. Our earlier studies demonstrated the ability of GdA to induce an intrinsic apoptotic cascade in CD4(+) T-lymphocytes and suppress the cytolytic effector function of CD8(+) T-lymphocytes. In this report, we investigated further into the mechanism of action of GdA controlling perforin and granzyme B expression in CD8(+) T-lymphocytes and the mechanism of action of GdA leading to lymphocyte death.
Flow cytometry analysis was performed to check for the surface expression of interleukin-2 receptor α (IL-2Rα) and intracellular eomesodermin (Eomes) in activated T-lymphocytes, whereas quantitative RT-PCR analysis was used to find out their mRNA profile upon GdA treatment. Western analysis was carried out to confirm the protein level of Bax and Bcl-2.
GdA reduces the surface expression of the high-affinity IL-2R complex by down-regulating the synthesis of IL-2Rα (CD25). This disturbs the optimal IL-2 signalling and decreases the Eomes expression, which along with IL-2 directly regulates perforin and granzymes expression. Consequently, the CD8(+) T-lymphocytes undergo growth arrest and are unable to mature into competent cytotoxic T-lymphocytes. In the CD4(+) T-lymphocytes, growth factor IL-2 deprivation leads to proliferation inhibition, decreased Bcl-2/enhanced Bax expression, culminating in mitochondrial stress and cell death.
GdA spurs cell cycle arrest, loss of effector functions and apoptosis in different T-cell subsets by making T-lymphocytes unable to respond to IL-2.
孕激素调节糖蛋白糖蛋白 A（GdA），在灵长类动物中，蜕膜化的子宫内膜以高浓度分泌，抑制母体对胎儿抗原的免疫反应，从而有助于正常妊娠中半同种异体胎儿的耐受。我们之前的研究表明，GdA 能够诱导 CD4(+)T 淋巴细胞发生内在凋亡级联，并抑制 CD8(+)T 淋巴细胞的细胞溶解效应功能。在本报告中，我们进一步研究了 GdA 控制 CD8(+)T 淋巴细胞中穿孔素和颗粒酶 B 表达的作用机制以及 GdA 导致淋巴细胞死亡的作用机制。
通过流式细胞术分析检查激活的 T 淋巴细胞表面白细胞介素 2 受体 α（IL-2Rα）和细胞内 Eomes 的表达，而定量 RT-PCR 分析用于发现 GdA 处理后的它们的 mRNA 谱。进行 Western 分析以确认 Bax 和 Bcl-2 的蛋白水平。
GdA 通过下调 IL-2Rα（CD25）的合成来减少高亲和力 IL-2R 复合物的表面表达。这扰乱了最佳的 IL-2 信号传导并降低了 Eomes 的表达，Eomes 与 IL-2 直接调节穿孔素和颗粒酶的表达。因此，CD8(+)T 淋巴细胞发生生长停滞并且无法成熟为有能力的细胞毒性 T 淋巴细胞。在 CD4(+)T 淋巴细胞中，生长因子 IL-2 的剥夺导致增殖抑制、Bcl-2 表达降低/ Bax 表达增强，最终导致线粒体应激和细胞死亡。
GdA 通过使 T 淋巴细胞无法响应 IL-2，促使不同 T 细胞亚群发生细胞周期停滞、丧失效应功能和凋亡。
